Cyclic-AMP signalling, MYC and hypoxia-inducible factor 1α intersect to regulate angiogenesis in B-cell lymphoma.
Cyclic-AMP signalling, MYC and hypoxia-inducible factor 1α intersect to regulate angiogenesis in B-cell lymphoma.
复制标题
环磷酸腺苷信号传导、MYC 和缺氧诱导因子 1α 交叉调节 B 细胞淋巴瘤的血管生成。
DOI：
10.1111/bjh.18196
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发表时间：
2022
影响因子：
6.5
通讯作者：
Aguiar,RicardoCT
中科院分区：
文献类型：
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作者：
Ethiraj,Purushoth;Sasi,Binu;Holder,KennethN;Lin,An-Ping;Qiu,Zhijun;Jaafar,Carine;Elkhalili,Alia;Desai,Parth;Saksena,Annapurna;Ritter,JacobP;Aguiar,RicardoCT
血管生成和MYC表达与弥漫性大B细胞淋巴瘤（DLBCL）的不良结局相关。MYC促进新血管系统发育，但其在DLBCL中的失调是否有助于血管生成尚不清楚。对这种关系的研究可能会发现DLBCL中新的致病调节回路以及抗血管生成策略。在这里，我们发现MYC表达与原发性DLBCL活检中血管内皮生长因子（VEGF）表达和血管生成呈正相关，与双重表达状态或细胞来源分类无关。我们发现MYC促进VEGFA表达，这一相关性在成熟B细胞肿瘤的大型数据集中得到了验证。使用DLBCL细胞系和患者来源的异种移植模型，我们确定了第二信使环AMP（cAMP）作为常氧条件下DLBCL中MYC表达、VEGFA分泌和血管生成的有效抑制剂。在缺氧中，cAMP转换靶点并抑制低氧诱导因子1α，低氧诱导因子1α是低氧环境中VEGFA/血管生成的主要调节因子。最后，我们使用磷酸二酯酶4 b（Pde 4 b）敲除小鼠来证明cAMP/PDE 4轴通过直接靶向淋巴瘤微环境来行使额外的抗血管生成作用。总之，MYC可以在DLBCL血管生成中发挥直接作用，并且可以用临床级PDE 4抑制剂实现的cAMP水平的调节在DLBCL中具有细胞和非细胞自主抗血管生成活性。
Angiogenesis and MYC expression associate with poor outcome in diffuse large B‐cell lymphoma (DLBCL). MYC promotes neo‐vasculature development but whether its deregulation in DLBCL contributes to angiogenesis is unclear. Examination of this relationship may uncover novel pathogenic regulatory circuitry as well as anti‐angiogenic strategies in DLBCL. Here, we show that MYC expression positively correlates with vascular endothelial growth factor (VEGF) expression and angiogenesis in primary DLBCL biopsies, independently of dual expressor status or cell‐of‐origin classification. We found that MYC promotes VEGFA expression, a correlation that was validated in large datasets of mature B‐cell tumours. Using DLBCL cell lines and patient‐derived xenograft models, we identified the second messenger cyclic‐AMP (cAMP) as a potent suppressor of MYC expression, VEGFA secretion and angiogenesis in DLBCL in normoxia. In hypoxia, cAMP switched targets and suppressed hypoxia‐inducible factor 1α, a master regulator of VEGFA/angiogenesis in low oxygen environments. Lastly, we used the phosphodiesterase 4b (Pde4b) knockout mouse to demonstrate that the cAMP/PDE4 axis exercises additional anti‐angiogenesis by directly targeting the lymphoma microenvironment. In conclusion, MYC could play a direct role in DLBCL angiogenesis, and modulation of cAMP levels, which can be achieved with clinical grade PDE4 inhibitors, has cell and non‐cell autonomous anti‐angiogenic activity in DLBCL.